The influence of CYP enzymes and ABCB1 on treatment outcomes in schizophrenia: association of CYP1A2 activity with adverse effects

Aim: Genetic variants on metabolic and transport enzymes are good candidates to explain inter-individual differences in response to antipsychotics. The aim of this study is to evaluate and compare the influence of the CYP2D6 , CYPC19, CYP1A2 and ABCB1 variants on plasma levels, treatment response and side effects of antipsychotics. Methods: Twenty polymorphisms in selected genes were genotyped in 318 patients diagnosed with schizophrenia, schizoaffective or delusional disorder treated with antipsychotics (clozapine, olanzapine, paliperidone, risperidone, aripiprazole and quetiapine). Plasma drug levels were determined after 6 weeks of treatment. The Positive and Negative Symptoms Scale (PANSS) and UKU scale of side effects were recorded at baseline and after 12 weeks of treatment. The effect of gene variants on plasma drug levels, treatment response and adverse effects were examined by multinomial regression. Results: CYP1A2 was found to be associated with psychic side effects (P = 0.02), with variants predicting higher enzyme activity associated with lower adverse effects, and was the strongest predictor for this adverse effect of all the studied factors. Functional variants in CYP genes were associated with plasma level differences, with higher activity variants associated with lower plasma levels. No association with improvement of the condition, as measured by the PANSS score, was found in this study. Conclusion: The results suggest that increased CYP1A2 activity protects against psychic side effects. Few studies have evaluated the impact of genetic factors on treatment response or side effects, and only in relation to a selection of adverse reactions. These results are a step towards better understanding of the factors behind the different aspects of clinical outcomes, such as various adverse effects.